Therapeutic system for the controlled release of active ingredients

ABSTRACT

A system designed to release one or more active substances in different, previously programmable modes, is described. The system is constituted by a tablet in three layers, two of which (the outer layers) vehicularise the active ingredient(s), whilst the third (the central layer) is constituted of a polymeric barrier which does not contain active substance and has the appropriate characteristics of erodibility or gelation. The tablet is completely coated with a film of polymeric material insoluble in water and/or in aqueous fluids, on which one or more incisions delimiting an area of exactly calculated geometric shape and size, have been made through the use of a laser beam of appropriate power and intensity. The removal of the film inside the incision(s) allows the release of the active ingredient(s) into aqueous fluid in predetermined amounts and umes. The procedure for the production of the aforementioned pharmaceutical form is also described.

STATE OF THE ART

In the last decades great importance has surrounded the research for theoptimisation of the release of active substances from matrices and/orother systems containing them, so that the activity is carried out inthe place and at the time desired. This problem finds many fields ofapplication but is above all relevant in the pharmaceutical sector bothfor human and veterinary use. It is relevant in the agricultural sectortoo, for example for the use of fertilisers, herbicides or selectivepesticides.

In the above indicated sectors, there is an enormous amount of researchand development attempting to guarantee the achievement of the releaseof active substances at controlled rate, independently of theenvironmental factors in which the matrix or the system containing theactive substance is found.

In the biomedical sector, there have been great advances, in theresearch and the developments of forms of administration or therapeuticsystems able to give up the active substance vehicularised in them at aconstant rate and for a period of time pre-determinable in vitro, withthe aim of obtaining identical or analogous behaviour in vivo.

The aim is that of achieving a system able to reach, and maintain overtime, predetermined plasma concentrations of active substances; suchsystems are classified as systems having a release kinetics defined as“zero order”.

The research in this sector has examined all the administration routesdestined for human therapy, but surely the sector in which there hasbeen the most activity is that of the oral administration systems; thisis due to the importance, both in terms of numbers and economics, of thepharmaceutical forms for oral administration in the global market, alsodue to the high degree with which oral administration is used amongpatients and to the undoubted advantages of stability showed by theactive substances when vehicularised in a solid pharmaceutical form suchas a tablet or a more sophisticated and complex therapeutic system, buthowever in the solid state.

Amongst the innovative, complex pharmaceutical forms for oraladministration, the therapeutic systems defined as osmotic pumps,usually indicated as OROS systems can be cited (U.S. Pat. No.4,160,020); which in fact refer to a system capable of releasing thedrug at constant rate over time.

The search for systems which are less complex and more manageable andeconomical to produce, has brought about the preparation and thecommercialisation of matrix based systems of particular geometry, suchas those claimed in the U.S. Pat. No. 5,422,123 and U.S. Pat. No.5,738,874. Other therapeutic systems designed for constant rate ofrelease of the active ingredient are described in “Novel Drug Delivery”by Prescott and Nimmo (J. Wiley—New York 1989), in “Controlled Releaseof drugs: Polymers and Aggregate Systems” M. Rosoff Ed. (VCH Pub. NewYork 1989) and in “Controlled release dosage form design” Cherngju KimEd. (Technomic - Lancaster 2000).

Above all in the treatment of chromic diseases, which in the majority ofcases involve elderly patients, the pharmaceutical forms and theembodiments described above have the undoubted advantage of allowing adrastic simplification of the dosage schemes with administrations which,in many cases, can be reduced to once a day, obtaining in addition agreater observance (compliance) by the patient of the prescribedtherapy.

The administration of constant release pharmaceutical forms isparticularly important if the active ingredient has an efficacioustherapeutic effect when plasma levels are achieved and maintained overtime which are defined in a precise “range”; below of which values thedrug is inactive, whilst at higher values are seen manifestations andside effects and/or toxic phenomena which, in some cases can beextremely dangerous.

It is however worth noting that not always and not for every disease isit necessary and appropriate to achieve and maintain constant plasmalevels of drug, in fact in certain diseases and in some symptomologieswith disease manifestations bound to chrono-biological rhythms it isfavourable to have pharmaceutical forms able to release the activeingredient in successive impulses so as to prevent giving rise to worsepain or pathological manifestations bound, as said above, to circadianrhythms.

Studies have in fact underlined that many functions of thecardiovascular, respiratory, renal and hepatic systems have importantvariations over the course of the day; the plasma concentrations of manyhormones such as insulin, cortisol, adrenaline, aldosterone, angiotensinand other substances such as glucose, plasma proteins and enzymes alsofollow circadian rhythms.

In addition the symptoms and the attacks of some diseases are notmanifested in a casual manner throughout the day. For example, asthmaattacks are more frequent during the night, myocardial infarction ismanifested with higher probability in the late morning, angina pectorisattacks are more frequent in the early hours of the morning, acutearthritis attacks are verified with greater frequency in the earlymorning as with the tremors typical of Parkinson's disease and thesymptoms of psychiatric disorders.

With such symptomologies the need for the availability of pharmaceuticalforms or therapeutic systems able to release the active ingredient ordifferent active ingredients in a pulsed manner, appears evident, i.e.to release doses of different drug(s) over time at programmable timeintervals.

An example of a system of pulsed release is that reported in theEuropean patent No. 0274734 in which is described a three layered tabletof which two are coated with a sheathing container constituted ofimpermeable polymer material and insoluble in water or soluble inalkaline environments. In the patented description and in the examplesaccompanying the patent are reported the preparation of a three layeredtablet of which the first and the third vehicularise the activeingredient, whilst the layer intermediate between them, is constitutedof gelable polymeric material. The sheath which coats the second and thethird layers and allows the immediate release of a first dose of drug,whilst the second portion is released after a time interval of approx.30 minutes characterises the system.

The system described in the above cited patent has however a dramaticlimitation in use, because the application of the coating is carried outmanually and each tablet is singularly subjected to the partial coatingprocedure through particularly long procedures, not easilystandardisable and however not transferable to the industrial scale.

Analogous limitations to the industrial feasibility are present in otherembodiments described in the European patent application No. 0788790 inwhich a nucleus with a partial external coating is disclosed, in whichsaid nucleus is of three layers of which the upper layer contains a doseof active substance, the intermediate layer is constituted of polymericmaterial with the function of a retardant barrier and the lower layercontains the remaining dose of active substance. The external coating isconstituted of polymeric materials applied by compression with a complexprocedure and not easily industrially applicable. A further improvementof the system described in the European patent application No. 0788790and reported in the patents U.S. Pat. No. 5,487,901 and U.S. Pat. No.5,650,169 in which is described a three layered tablet completely coatedby a film of impermeable polymeric material a part of which iseliminated by an abrasion process: with the abrasion of the coating wasalso abraded and eliminated a part of the layer which contains theactive substance thus giving rise to a possibly inferior activesubstance content to the minimal limit necessary for the therapy orhowever a loss of active substance.

SUMMARY OF INVENTION

A new programmed release therapeutic system has now been foundconstituted of a three layered tablet completely coated by a filminsoluble in aqueous fluids on which incisions have been made by laserbeams which delimit one or more surfaces of predetermined shape andsize, removable when the therapeutic system comes into contact withaqueous fluids, releasing the corresponding surface(s) of the tablet.With the system according to the present invention after the release ofthe first dose, the latency time for the release of the second dose ofthe same or a different active ingredient can be programmed in a preciseinterval of time, from 15 minutes to 6-10 hours.

The fact that the procedure for the preparation of the above mentionedtherapeutic system uses production technologies of use widelyconsolidated and such as to allow the regulated and standardisedpreparations of the pulsed release pharmaceutical form, in particularthe laser technology is particularly important.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: cross sectional view of a rounded shape three-layered tabletshowing the outer layers (1) and (2) comprising the activeingredient(s), and the inner barrier layer (3), completely coated by thefilm coating (4), on which one or more incisions has to be made.

FIG. 2: cross sectional view of the tablet in FIG. 1, showing oneincision (5) only on a face of the coating.

FIG. 2: cross sectional view of the tablet in FIG. 1, showing twoincisions (5) on the faces of the coating.

DETAILED DESCRIPTION OF THE INVENTION

The present invention refers to release system comprising a tablet ornucleus comprising at least three completely overlying layers,completely coated with a film insoluble in aqueous fluid. Of theselayers which constitute the tablet (nucleus):

-   -   the first layer contains one or more active substance formulated        so as to be released rapidly or in a gradual manner;    -   the second layer, the barrier layer, is formulated so as to        constitute a “barrier” to the release of the active substance        vehicularised in the third layer. Such barrier layer has        fundamentally the role of rendering independent the release of        the first and the third layer. Furthermore it is able to slowly        interact (in a time interval programmable by in vitro tests)        with the means of dissolution (aqueous and/or characterised by        different pH values), therefore protecting the third layer for a        predeterminable period of time from contact with the means of        dissolution until said means of dissolution penetrates through        the aperture in the coating of the first layer;    -   the third layer contains one or more active substance, identical        or different to that contained in the first layer, formulated in        a manner such as to be released rapidly or slowly both if placed        directly in contact with the aqueous fluid, and after the        erosion of the barrier layer, which separates the third layer        from the first.

In the preferred embodiment the tablet is as schematically reported inFIG. 1, i.e. of rounded shape.

The first and the third layer, which contain the active substance, canbe identical or different compositions and thickness. The thickness ofthe two layers vary depending on the active substances and of the othercomponents vehicularised in it.

The above described tablet of the invention is completely and uniformlycoated by a filming procedure in a shallow basin or by anotherindustrially applicable procedure, with appropriate coatings whichimpede the release of the active ingredient. Preferably, such coatingfilms are insoluble and impermeable to aqueous liquids in the pHinterval of between 1.2 to 9.

A fundamental characteristic of the system of the invention is the factthat the insoluble film coating is etched by a laser beam of appropriatepower and intensity, applied for an interval of time determineddepending on the characteristics and the thickness of the coating. Thelaser beam creates, in the coating, one or more incisions which delimita surface of geometrical shape and of an area predetermined with extremeprecision. It is possible to make such incisions with precision suchthat only the insoluble coating is notched without interfering with theunderlying tablet. The contact of the new release system with water orwith biological fluid determines the infiltration of the fluid throughthe incision(s) and therefore the beginning of the erosion or the slowgelation of the constituents of the matrix system of the nucleus withthe consequent raising of the parts of the film around the incision(s).The portion of insoluble coating delimited by the incision(s) breaks offallowing the interaction between the means of dissolution and thenucleus containing the active substance through the surfaces of thenucleus remaining uncovered. The coating, in addition, remains intactuntil the moment of use and is partially removed only in vivo, so thatit protects the active ingredients contained in the tablet from humidityand oxidation, thus increasing the stability and conferring to thetablet an optimal mechanical resistance.

In any case, the interaction with the means of dissolution and therelease of the active ingredient can take place only through the holemade in the coating, at a rate which depends on the area exposed and istherefore exactly predeterminable. The therapeutic release systemaccording to the present invention is extremely flexible and allows apulsed release of active ingredients according to various alternativeswhich allow to satisfy the most different dosage needs.

The incision can delimit an area of said coating of dimensions rangingbetween 2 and 50% and preferably between 5 and 30% of the total area ofthe coating.

According to a first embodiment of the invention the incision(s) in thecoating are made on the face of the tablet which is found correspondingto the first layer.

When the system is used, the interaction of the nucleus with the meansof dissolution—and therefore the release of the active substancevehicularised in the first layer—can take place only through the surfacedevoid of coating. Upon contact with water or with biological fluids thefirst dose of drug begins to be released through the hole(s) made in thecoating, at a rate which depends on the area exposed and therefore, inthe case in which the hole(s) are circular, on the diameter of thehole(s). A the end of the programmed release of the first dose, thepresence of the barrier layer impedes the release of the second dose ofdrug as long as the barrier itself will not have been eroded ordisaggregated by the means of dissolution. Therefore the characteristicsof the barrier, and in particular the necessary time for its erosion ordisaggregation, determine the duration of the time interval between therelease of the first dose of drug and of the second dose. If the activeingredient is the same in the first and in the third layer one will havethe pulsed release of a single drug with a time interval between thefirst and second delivery exactly programmable.

The embodiment described above is schematically represented in FIG. 2,which shows a tablet or nucleus with a portion of the surfacecorresponding to the incision in the coating corresponding with thefirst layer immediately available for contact with aqueous liquids andtherefore with the active ingredient contained in said rapidlyreleasable layer, whilst all the remaining portion of the tablet(corresponding to the second layer-barrier and to the third layer) ishomogeneously and regularly coated.

According to a further embodiment of the invention it is possible tohave different active ingredients in the first and in the third layerand the incision of the soluble coating layer made only incorrespondence with the first layer of the tablet (nucleus). With such asystem the administration of two different drugs is possible, with apredetermined time interval and with a release passage which can beregulated by the composition of the first and of the third layer whichcontains the two different active ingredients and which can bedifferent.

According to a further embodiment of the invention it is possible tohave different active ingredients in the first and in the third layerand cut with the laser the insoluble coating film, both incorrespondence with the first and with the third layer. In such a caseit is possible to administer simultaneously two different activeingredients with different release kinetics which can be regulated bothas a function of the composition of the layer and as a function of theshape and dimension(s) of the apertures made in the coating by laserincision (see FIG. 3).

According to a further embodiment of the present invention on the filmedtablet which has one or more incisions a second gastroresistant andenterosoluble polymeric coating is applied. This allows a furthercontrol of the release because in a gastric environment the activesubstance vehicularised in the tablet is not released and the systemactivates only at the enteric level, when the enterosoluble coatingundergoes solubilisation. The release of the vehicularised activeingredient begins only following such solubilisation and will be onlythrough the hole(s) made in the coating of impermeable polymericmaterial.

This configuration of the tablet allows the active substance to bereleased only at the enteric level and can be used to obtain the releaseof the drug up to the distal portion of the enteric tract, for a releaseat the level of the colon or the rectum.

Schematically the composition which constitutes the nucleus of therelease system according to the invention can be thus described:

First Layer

If a rapid release of the active substance is desired, the compositionof the first layer comprises polymeric substances capable of favouringthe disintegration of said layer, thus facilitating the dissolution andthe rapid release of the active ingredients vehicularised in it. Forexample, said polymeric substances can be selected from the groupconsisting of cross linked polyvinylpyrrolidone, sodium amidoglycolate,carboxymethylcellulose, salts and derivatives thereof, cross linkedsodium carboxymethylcellulose, polyoxyethylene, carboxymethylamide,hydroxypropylcellulose and low and medium molecular weighthydroxypropylmethylcellulose, potassium methacrylate-divinylbenzeneco-polymer, polyvinylalcohols, glucan, scleroglucan, mannan, starches,starch derivatives, microcrystalline cellulose and cellulosederivatives, beta cyclodextrin and dextrin derivatives in general. Asfar as hydroxypropylmethylcellulose is concerned, various types can beused with different molecular weights (from 1000 to 4000000) and withdifferent degrees of substitution. These types ofhydroxypropylmethylcellulose have different characteristics and may beprevalently erodible or prevalently gelable, as a function of the degreeof substitution (D.S.) in the polymeric chain.

Also, as far as the polyoxyethylenes are concerned, various types withdifferent molecular weights (from 1000 to 4000000) can be used and withdifferent properties: they can be prevalently erodible or prevalentlygelable, as a function of the molecular weight of the polymeric chain.

The polymeric substances constitute from 1 to 90% of the weight of thelayer, preferably from 5% to 60%.

In addition the so called effervescent mixtures can be used, capablethat is of producing the rapid disintegration of the tablet or, in thespecific case, of the layer when it comes into contact with aqueousliquids or with gastric juices.

These effervescent mixtures may comprise mixtures constituted of acidssuch as citric, tartaric, fumaric acids and carbonates and bicarbonatesof sodium and other alkaline or alkaline earth metals, glycocoll, sodiumcarbonate and other pharmaceutically acceptable salts, capable ofdetermining the appearance of the “effervescence” and the rapiddisintegration of the compacted matter.

Other coadjuvant substances, selected from the group comprisingsubstances normally used in the pharmaceutical field, such as diluents,buffers, binding agents, adsorbents etc. can also be used, and inparticular starch, pre-gelatinised starch, calcium phosphate, mannitol,lactose, sucrose, glucose, xylitol, sorbitol, microcrystalline celluloseand binding agents such as gelatine, polyvinylpyrrolidone,methylcellulose, starch indicator, ethylcellulose, gum arabic, andtragacanth gum.

In addition, other excipients normally used in pharmaceutical techniquescan be used as coadjuvants such as magnesium stearate, calcium stearate,sodium fumarate, stearic acid, talc, colloidal silica, glycerylmonostearate, polyethylene glycols of molecular weights from 200 to20000, hydrogenated castor oil, waxes and mono-di- and tri- substitutedglycerides.

If instead a slow release of the active substance contained in the firstlayer is desired, excipients able to slow down the hydration anddisiritegration and/or to favour the slow erosion of said layer can finduse, slowing down in such a manner the dissolution and the release ofthe first dose of active substance contained in said layer. In theexamples attached to the present application will be better highlightedthe characteristics of said layer.

The thickness of the first layer ranges between 0.5 and 5.0 mm.

Second Layer (Barrier)

In the case of the configuration of the system as described in FIG. 2,the formulation of the “barrier” layer—which allows the determination ofthe time interval necessary for the liberation of the active ingredientcontained within the third layer—comprises polymeric substances,preferably in association with coadjuvants and plasticising substances.

The polymeric substances of the barrier layer can be selected, forexample, from the group consisting of hydroxypropylmethylcellulose withmolecular weight ranging between 1000 and 4000000,hydroxypropylcellulose with molecular weights ranging between 2000 and2000000, polyoxyethylenes (PEO) with molecular weights ranging between1000 and 10000000, carboxyvinyl polymers, polyvinyl alcohols withmolecular weights ranging between 10000 and 1000000, polyamides,polyanhydrides, polyvinylpyrrolidone, glucans, scleroglucans, mannans,xanthans, carragenans, galactomannans, gellans, polyaminoacids,poly(methyl vinyl ethers/ maleic anhydride), carboxymethylcellulose andderivatives, ethylcellulose, methylcellulose, cellulose derivatives ingeneral, alginic acid and salts and derivatives thereof, starches,starch derivatives, □-, □-, □-cyclodextrines and copolymers of the abovementioned polymers.

The polymeric substances are present in percentages of between 5 to 90%with respect to the total weight of said layer and preferably from 30%to 90%.

The coadjuvant substances can be selected, for example, from the groupconsisting of glyceryl monostearate and semi synthetic triglyceridederivatives, semi-synthetic glycerides, hydrogenated castor oil,glycerylpalmitoylstearate, glyceryl beenate, cetyl alcohol,polyvinylpyrrolidone, ethylcellulose, methylcellulose, sodiumcarboxymethylcellulose, and other natural or synthetic substances wellknown to all the experts in the art. For example magnesium stearate,stearic acid, talc, sodium benzoate, boric acid, polyethyleneglycols andcolloidal silica are used.

In addition, diluents, binding agents, lubricants, buffers,antiadherents, glidants and other substances capable of conferring thedesired characteristics to said layer can be used, as will become betterexplained in the examples outlined below.

Also, other pharmaceutically acceptable substances capable of favouringthe compressibility of the mixture and/or of optimising the productionprocess can find use; such substances have the function of conferringonto the barrier layer the necessary elasticity and of improving theadhesion, cohesion and resistance characteristics.

The coadjuvant substances, in association with the previously reportedpolymeric materials, are capable of better defining the period of“holding” of the barrier; allowing such interval to vary from 15 minutesup to 6-10 hours according to the required therapeutic necessity.

The barrier layer, as reported above and as will be underlined better inthe examples accompanying the present invention, can be constituted ofpolymers predominantly erodible and/or soluble in water and in aqueousliquids.

When however, the therapeutic requirements require that the second doseof drug or, however, that the active substance contained in the thirdlayer must be released slowly and in a gradual manner, after adetermined period of time from the release of the first dosage, thensaid barrier layer will be preferably constituted of predominantlygelable polymers. Operating thusly, it is possible to obtain a rapidrelease of the first dose of drug and, following a defined timeinterval, the release of the second dose which, proceeding gradually andat a rate programmable in vitro, guarantees the maintenance ofefficacious plasma levels of the drug.

Analogously, if the system of the invention has a configuration asreported in FIG. 3, the barrier layer can be predominantly constitutedof hydrophilic and gelable polymeric materials, the barrier in this casehaving the function of separating the first and third layers whichcontain different active substances and which can be incompatible witheach other.

The thickness of said second layer (barrier) is comprised of between 0.5and 5.0 mm.

Third Layer

The third layer can be constituted of an identical or differentformulation from that adopted in the first layer. In addition, the thirdlayer can contain identical active ingredient(s) or can vehicularisedifferent active ingredient(s): in this case the system has aconfiguration as reported in FIG. 2.

Alternatively, the third layer can vehicularise one or more activeingredients different from these vehicularised in the first layer,giving the system a configuration as reported in FIG. 3. In this case,the active ingredient(s) of the third layer is released simultaneouslywith the active ingredients contained in the first layer at a rate whichwill depend on the composition of the layer itself.

The thickness of said third layer is comprised of between 0.5 and 5.0mm.

Coating

The fundamental characteristics of the system described is constitutedby the fact that all the three layered tablets are completely coated,according to procedures known in the art (in shallow basins, influidised beds or with other procedures), with a layer (film) ofpolymeric material which is impermeable to water or to aqueous fluids,at least for a period of time such as to allow both the release of thefirst dose of active ingredient and the dissolution of the secondbarrier layer prior to the release of the second dose of activeingredient.

Such filming agents, for example, ethylcellulose (of different molecularweights) and acrylic and methacrylic polymers can find use.

According to an embodiment of the present invention onto the filmedthree layered tablet which has one or more incisions in the insolublecoating, as described above, can also be applied a secondgastroresistant and enterosoluble polymeric coating. Such a coating canbe constituted for example of acrylic and methacrylic copolymers,cellulose acetate-phthalate, cellulose acetate-propionate, cellulosetrimellitate and other natural synthetic or semi-synthetic cellulosederivatives, of hydroxypropylcellulose, of hydroxypropylmethylcellulose,for example hydroxypropylmethylcellulose acetate succinate.

In the filming operation of the three layered tablet coadjuvants such ascolouring agents, opacifying and plasticising substances such astriethylcitrate, diethylphthalate, butyl phthalate, diethylsebacate,polyoxyethyleneglycols of molecular weights ranging between 300 and50000 can find use.

The thickness of the coating film may range from 5 to 1000 □m butpreferably from 20 to 500 □m.

The claimed system is characterised by the fact that the insolublecoating film has one or more incisions delimiting an area ofappropriately calculated geometric shape and dimensions.

The incision in the coating film can be carried out on only one face ofthe system (as schematically represented in FIG. 2) so as to allow, asalready said, contact of the means of dissolution in vitro or ofbiological fluids in vivo only with the first layer containing the firstmedication.

Alternatively, the incision in the coating film can be carried out onboth faces of the system (as schematically represented in FIG. 3) so asto allow contact with the means of dissolution simultaneously with theactive ingredients contained in the first and third layers.

To carry out the incision operation in the coating film a laser beam ofappropriate energy and intensity is used; it is applied for an intervalof time defined on the basis of the characteristics and the thickness ofsaid film, as will be better explained in the following Examples.Preferably the incision in the coating film is performed using a CO₂source laser apparatus having a power of 20 W.

The laser beam provokes a precise incision in the coating filmdelimiting an area of geometrical shape (a circle in the most simplecase) and of predetermined dimensions in function to the flow of drugdesired per unit of time.

Operating as indicated above one can obtain filmed tablets, coated allover the surfaces with the exception of one or two portions of thesurfaces exactly defined and measurable, as schematically reported inFIGS. 2 and 3, for non limiting illustration of the invention. Thatmeans that all the surfaces of the tablet are impermeable to aqueousliquids with the exclusion of the only surface devoid of coating. Infact, the incision in the coating film allows the penetration into thenucleus of the dissolving liquid. The contact with aqueous liquid orwith biological liquids allows the activation of the system and beginsthe release of the active substance(s) vehicularised in the system.

Amongst the active substances of possible use in the present system canbe listed all the active substances able to carry out their curativeand/or protective action towards the disease manifestations which aremanifested according to temporal and in particular to circadian rhythms,for example: non steroid anti inflammatory substances (NSAID) such assodium diclophenac, indomethacin, ibuprofen, ketoprofen, diflunisal,pyroxicam, naproxene, flurbiprofen, sodium tolmethin, paracetamol, antiinflammatory steroids or sleep inducing substances and tranquilliserssuch as diazepam, nitrazepam, flurazepam, oxazepam, chlordiazepoxide,medazepam, lorazepam, active ingredients for the control of hypertensionsuch as amlodipine, captopril, clonidine, dilthiazem, enalapril,felodipine, katanserine, lisinopril, methyidopa, nifedipine,nitrendipine, nicardipine, prazosine, ramipril, beta blockers such asatenolol, metoprolol, pindolol, propanolol, timolol, diuretics such asamiloride, clortalidone, frusemide, hydrochlorotiazide, indapamide,spironolattone, anti Parkinson's drugs such as amantidine, bromocriptin,levodopa, antihistamines such as tripelennamine, terfenadine, antiasthmatics such as ketothiophene, nedocromil, antibiotics alone and inassociation or chemotherapeutic agents.

The tablets of the invention can be produced, starting from mixtures ofpowders and/or granulates, using the current production technologies andtherefore with production processes immediately scalable to theindustrial level.

For example, they can be produced using rotary pressing machinessuitable for producing “multi-layered” tablets such as for exampleElisabeth Hata, Korsch or Manesty Layer-press. Normally, the workingpressure varies from 1000 to 5000 kg, obtaining according to theprocedure better detailed in the following Examples, three layeredtablets spheroid, ovoid in shape and, however, without notable spikes,such as to allow said pharmaceutical forms to be subjected to thesuccessive filming process using known technologies such as coating inshallow basins or in fluidised beds.

The following examples are reported as non limiting illustrations of thepresent invention.

EXAMPLE 1

The preparation of a series of 5000 three layered tablets as reported inFIG. 2, containing as the active ingredients in the first and thirdlayer diltiazem (two doses of 60 mg each) and an intermediate barrierlayer.

1.a Preparation of the Granulate Containing the Active IngredientDiltiazem (Profarmaco -Milan)  60.0 mg Corn starch (USP grade, C Erba,Milan, I)  30.0 mg Lactose (USP grade, C Erba, Milan, I)  40.0 mgMethylcellulose (Methocel ® A4-  0.2 mg Colorcon - U.K)Polyvinylpyrrolidone (cross linked)(Polyplasdone  10.0 mg ISP-Wayne, NY,USA) Sodium carboxymethylamide (Explotab ® -  10.0 mg E. Mendell USA)Magnesium stearate (C Erba, Milan, I)  1.0 mg Colloidal silicate(Syloid ® 244,  0.5 mg Grace GmbH, Worms, D Total 151.7 mg

The envisaged quantity of diltiazem is mixed, in an appropriate mixer,with the lactose and the corn starch; the homogeneous mixture obtainedis wetted with an aqueous solution of 1.3% methylcellulose in water. Theuniformly humidified mass is forced through a grid of 25 mesh (equal to710 microns) obtaining a granulate which is dried in a hot aircirculating oven until a constant weight. The dried granulate, isre-calibrated through the same grille, has the disaggregants, themagnesium stearate and the colloidal silicate added. The mass is mixedin a V shaped mixer for 30 minutes.

The granulate thus obtained is used for the preparation of the first andthe third layer, as will be described in detail in the following point1.c.

1.b—Preparation of the Granulate for the Production of the Barrier Layer

The granulate has the following percentage composition:Hydroxypropylmethylcellulose (Methocel ® E5 75.5% Colorcon -U.K.)Hydrogenated castor oil (Cutina ® HR - 3 Henkel -D) 18.8%Polyvinylpyrrolidone (Povidone ISP-Wayne, NY, USA)  2.8% Blue laquer(Colorcon ® -U.K)  0.1% Magnesium stearate (C Erba, Milan, I)  1.9%Colloidal silica (Syloid ® 244, Grace GmbH, Worms, D  0.9% Totale  100%

The envisaged amount of hydroxypropylmethylcellulose and hydrogenatedcastor oil are mixed, in an appropriate mixer, with the blue laquercolouring; the homogeneous mixture obtained, lightly blue coloured, ishumidified in a hydroalcoholic solution of 10% polyvinylpyrrolidone. Theuniformly humid mass is forced through a 25 mesh grille (equal to 710□m) obtaining a granulate which is dried in a hot air circulating ovenuntil constant weight. The dried granulate, re-calibrated through thesame grid, is added with magnesium stearate and colloidal silicate.

The mass is mixed in a V shaped mixer for 30 minutes.

The granulate thus obtained is used for the preparation of the secondlayer, as will be described in detail in the following example 1.c.

1.c—Preparation of the Three Layered Systems (by Compression).

The granules obtained according to such procedures outlined andaccording to schemes well known to any person skilled in the art, areloaded into the three loading hoppers of a rotary press suitable forproducing three layered tablets (e.g. Manesty Layer-Press, Liverpool,UK). In particular into the first and third hopper is loaded thegranulate described in point 1.a; whilst in the second hopper is loadedthe granulate according to that described in the preceding example 1.b.

The pressing machine is equipped with rounded circular dies of 10.0 mmdiameter and a radius of curvature of 12 mm; thus allowing theattainment of circular rounded tablets.

The machine is set up so as to produce three layered overlaid systemsconstituted respectively of 151.7 mg of granulate containing the activeingredient (equal to 60 mg of diltiazem) 150.0 mg of granulate preparedin example 1.b (such a quantity being necessary to obtain a layer ofapprox. 1.5 mm in thickness) and a second dose of 151.7 mg of granulatecontaining the active ingredient.

Operating as previously described, three layered tablets having a meanweight of 453.4 mg, containing two distinct doses of 60 mg activeingredient, are obtained.

1.d—Filming Coating

The tablets thus obtained are subjected to filming in a basin using anaqueous coating dispersion the percentage composition of which w/w isdescribed as follows.

Copolymer of Acrylic and Methacrylic Acid (Eudragit ® L 30 D - Rohm -Pharma -D) 17.5% Talc(C. Erba, Milan, I)  5.3% Triethylcitrate (C. Erba,Milan, I)  1.7% Titanium dioxide (C. Erba, Milano, I)  5.3% Water 70.2%Total  100%

The filming operation is carried out in a traditional stainless steelbasin 30 cm in diameter; the solution of the polymeric coating materialis sprayed with a traditional air jet system (Asturo Mec type withnozzles from 1.0 mm). The filming operation is carried out until theapplication of a continuous, homogeneous and regular coating film isachieved for each tablet with a thickness of approx. 100 □m.

Operating-according to the above described procedure, completely coatedthree layered tablets, as highlighted in FIG. 1, are obtained.

1.e—Incisions of the Film Coating (With Circular Incisions of 5.0 mm inDiameter Delimiting a Surface Coating of 19.6 mm²).

The filmed tablets are placed in an appropriate vibrator-distributorwhich orient and distribute the tablets singularly on suitably precisehousings with calibrated dimensions. A transport system allows thecarrying of the single tablets positioned on the maximal stabilitysurface under the ablation system constituted of a CO₂ laser beam sourcewith a power rating of 20 W which carries out the removal of a portionof the film. In particular on the upper face of the filmed tablet isperformed a circular incision of 5.0 mm in diameter.

The incision is carried out in a time of around 100 milliseconds, anapplication necessary and sufficient to perforate the coating film of athickness of about 100 □m.

Operating as described above filmed tablets coated in every part of thesurface are obtained, with the exception of the surfaces cut by laserbeam as described in FIG. 2. That means that all the coated surfaces ofthe tablet are impermeable to aqueous liquids with the exclusion of thecut surfaces.

1.f—Dissolution Test

To evaluate the release characteristics of the finished system,described in example 1.e (the circular incision of the film of 5.0 mm indiameter) is used the apparatus 2, paddle (described in USP XXII)operating at 100 r.p.m. and using such a dissolution fluid as 0.1 Nhydrochloric acid at 37° C. The release of the active ingredient isfollowed by UV spectrophotometric determination at 236 nm using anautomatic sampling and reading system (Spectracomp 602 from AdvancedProducts-Milan)

The results of the test carried out are reported in table I TABLE I Time(min) % release  15 30.2  30 48.7  60 50.8 120 51.0 240 51.3 360 51.5480 52.8 600 98.7 720 100.9

From the results highlighted in the Table above, it is evident that arapid release of the first dose (50% of the total dose contained in thesystem) occurs within 30-60 minutes, followed by an interval of around 9hours during which drug is not released, and then release of the seconddose of active ingredient following 10 hours from the beginning of thedissolution test. Such behaviour fully answers the objectives of thepresent invention.

EXAMPLE 2

Preparation of a series of 5000 filmed three layered tablets asdescribed in FIG. 2, containing as the active ingredient in the firstand third layer diltiazem (two doses of 60 mg each) and an intermediatebarrier layer.

The preparation of the filmed tablets is carried out using the proceduredescribed in example 1 up to point 1.d. The peculiarity of Example 2lies in the different dimensions of the coating surface delimited by theincisions.

2.e—Incision of the Film Coat (With a Circular Incision of 7.0 mm inDiameter Delimiting a Coating Surface of 38.5 mm²)

The filmed tablets are placed in an appropriate vibrator-distributorwhich orients and distributes the tablets singularly on suitably precisehousings with calibrated dimensions. A transport system allows thecarrying of the single tablets positioned on the maximal stabilitysurface under the ablation system constituted of a CO₂ laser beam sourcewith a power rating of 20 W which carries out the removal of a portionof the film. In particular on the upper face of the filmed tablet isperformed a circular incision of 7.0 mm in diameter.

The incision is performed in a time of around 100 milliseconds, theapplication necessary and sufficient to perforate the coating film witha thickness of approx. 100 □m.

Operating as described above, filmed tablets coated on every part oftheir surfaces are obtained, with the exception of the surfaces cut bythe laser beam as described in FIG. 2. That means that all the coatedsurfaces of the tablet are impermeable to aqueous liquids with theexception of the cut surfaces.

2.f—Dissolution Test.

To evaluate the release characteristics of the finished systems,described in example 2.e (with a circular abrasion of 7.0 mm indiameter) is used the apparatus 2, paddle (described in USP XXII)operating at 100 r.p.m. and using 0.1 N hydrochloric acid at 37° C. assuch dissolution fluid. The release of the active ingredient is followedby UV spectrophotometric determination at 236 nm using an automaticsampling and reading system (Spectracomp 602 from Advanced Products,Milan).

The results of the test performed are reported in Table II TABLE II Time(min) % released  15 39.6  30 51.1  60 52.0 120 52.6 240 53.3 360 68.5420 95.8 480 101.3

From the results in the Table above, it is evident that a rapid releaseof the first dose (50% of the total dose contained within the system) isobtained in 15-30 minutes, followed by an interval of around 5-6 hoursduring which drug is not released and by the release of the second doseof the active ingredient after around 6-7 hours from the beginning ofthe dissolution test. Such behaviour fully answers the objectives of thepresent invention.

EXAMPLE 3

The preparation of a series of 5,000 filmed three layered tablets asdescribed in FIG. 2, containing as the active ingredient in the firstand third layer diltiazem (two doses of 60 mg each) and an intermediatebarrier layer.

The preparation of the filmed tablets is carried out using the proceduredescribed in example 1 up to point 1.d. The peculiarity of Example 3lies in the different dimensions of the coating surface delimited by theincisions.

3.e—Incision of the Film Coating (With Circular Incisions of 9.0 mm inDiameter Delimiting 63.6 mm² of Surface)

The filmed tablets are placed in an appropriate vibrator-distributorwhich orients and distributes the tablets singularly on suitably precisehousings with calibrated dimensions. A transport system allows thecarrying of the single tablets positioned on the maximal stabilitysurface under the ablation system constituted of a CO₂ laser beam sourcewith a power rating of 20 W which carries out the removal of a portionof the film. In particular, on the upper face of the filmed tablet isperformed a circular incision of 9 mm in diameter equal to 63.6 mm² ofsurface.

The incision is performed in a time of around 100 milliseconds, theapplication necessary and sufficient to perforate the coating film of athickness of approx. 100 □m.

Operating as described above, filmed tablets coated on every part oftheir surfaces are obtained, with the exception of the surfaces cut asdescribed in the FIG. 2. That means that all the coated surfaces of thetablet are impermeable to aqueous liquids with the exception of the cutsurfaces.

3.f—Dissolution Test

To evaluate the release characteristics of the finished systems,described in Example 3.e (with circular incisions of 9.0 mm in diameter)is used the apparatus 2, paddle (described in USP XXII) operating at 100r.p.m. and using 0.1 N hydrochloric acid at 37° C. as such dissolutionfluid. The release of the active ingredient is followed by UVspectrophotometric determination at 236 nm using an automatic samplingand reading system (Spectracomp 602 from Advanced Products, Milan).

The results of the tests carried out are reported in table III TABLE IIITime (min) % release  5 23.0  15 40.6  30 50.9 120 51.2 180 72.7 24097.0 300 99.8

From the results in the Table above, it is evident that a rapid releaseof the first dose (50% of the total dose contained within the system)occurs in 15-30 minutes, followed by an interval of around 2.5-3 hoursduring which no drug is released and by the release of the second doseof the active ingredient after approx. 4 hours from the start of thedissolution test. Such behaviour fully answers the objectives of thepresent invention.

EXAMPLE 4

The preparation of a series of 5000 three layered tablets as describedin FIG. 2, containing such active ingredient in the first and thirdlayer diltiazem (the first dose of 50% and the second dose of 50%) andan intermediate barrier layer.

The barrier layer differs with respect to the previous examples in thatHydroxypropylmethylcellulose (Methocelo® E3) having lower molecularweight and viscosity is used.

4.a—Preparation of the Granulate Containing the Active IngredientDiltiazem (Profarmaco -Milan)  60.0 mg Corn starch (USP grade, C Erba,Milan, I)  30.0 mg Lactose (USP grade, C Erba, Milan, I)  40.0 mgMethylcellulose (Methocel ® A4-  0.2 mg Colorcon - U.K)Polyvinylpyrrolidone (cross linked) (Polyplasdone  10.0 mg ISP-Wayne,NY, USA) Sodium carboxymethylamide (Explotab ® -  10.0 mg E. MendellUSA) Magnesium stearate (C Erba, Milan, I)  1.0 mg Colloidal silicate(Syloid ® 244, Grace  0.5 mg GmbH, Worms, D Total 151.7 mg

The envisaged amount of diltiazem is mixed, in a appropriate mixer, withthe lactose and the corn starch; the homogeneous mixture obtained ishumidified with an aqueous solution of 1.3% methylcellulose in water.The uniformly humid mass is forced through a 25 mesh grid (equal to 710□m) obtaining a granulate which is dried in a hot air circulating ovenuntil constant weight. The dried granulate, re-calibrated through thesame grille, is added to the disaggregants, the magnesium stearate andthe colloidal silicate. The mass is mixed in a V shaped mixer for 30minutes.

The granulate thus obtained is used for the preparation of the first andthird layer, as will be described in detail in the following example4.c.

4.b—Preparation of the Granulate for the Production of the Second Layer(Barrier Layer)

The granulate has the following percentage compositions:hydroxypropylmethylcellulose (Methocel ® E3  76.5% Colorcon ® -U.K.)Hydrogenated castor oil (Cutina ® HR - Henkel -D)  19.0%Polyvinylpyrrolidone (Povidone ISP-Wayne, NY, USA)  2.9% Green laquer(Aluminium oxide)  0.1% Stearic acid (C Erba, Milan, I)  1.5% Total100.0%

The envisaged amount of hydroxypropylmethylcellulose and of hydrogenatedcastor oil is mixed, in an appropriate mixer, with the green colouredlaquer; the homogeneous mixture obtained, lightly green in colour, ishumidified with an hydroalcoholic solution of 10% Polyvinylpyrrolidone.The uniformly humidified mass is forced through a 25 mesh grid (equal to710 □m) obtaining a granulate which is dried in a hot air circulationoven until constant weight. The dried granulate, re-calibrated throughthe same grille, is added to the stearic acid. The mass is mixed in a Vshaped mixer for 30 minutes.

The granulate thus obtained is used for the preparation of the secondlayer, as will be described in detail in the following example 4.c.

4.c—Preparation of the Three Layered Systems (by Compression).

The granulates obtained according to the above described procedures andwell known in the art, are loaded into three loading hoppers of a rotarypress suitable for producing three layered tablets (e.g. ManestyLayer-Press, Liverpool, UK). In particular in the first and third hopperare loaded the granulate described in Example 4.a; whilst in the secondhopper is loaded the granulate according to the procedure described inthe preceding Example 4.b.

The machine press is equipped with rounded circular dies of 10.0 mm ofdiameter and a radius of curvature of 12 mm, thus allowing theattainment of rounded circular tablets.

The machine is set up such as to produce three layer systems constitutedrespectively of 151.7 mg of granulate containing the active ingredient(equal to 60 mg of diltiazem), 50.0 mg of the granulate prepared inExample 4.b (such a quantity being necessary to obtain a barrier layerwith a thickness of 1.5 mm approx.) and of 151.7 mg of the granulatecontaining the active ingredient (equal to 60 mg of diltiazem).

Operating as previously described, three layered tablets of mean weightof 453.4 mg containing two distinct doses of the active ingredient of 60mg each, are obtained.

4.d—Coating for Filming.

The tablets thus obtained are subjected to filming in basins using anaqueous coating dispersion the percentage composition of which w/w isreported as follows. Dispersion of ethylcellulose (Surelease ® clear 60.0% Colorcon ® U.K.) water  40.0% Total 100.0%

The filming operation is performed in a traditional stainless steelbasin 30 cm in diameter; the dispersion of polymeric coating material isconstituted of ethylcellulose and contains such diethylsebacateplasticising agents and oleic acid as stabiliser; the dispersion,diluted in water prior to use, is sprayed with a traditional air jetsystem (Asturo Mec type with nozzle from 1.0 mm). The filming operationis carried out until the application of a continuous, homogeneous andregular film coating for each tablet.

One obtains, operating in the described manner completely coated threelayered tablets, as highlighted in FIG. 1.

4.e—Incisions in the Film (With Circular Incisions of 7.0 mm in DiameterDelimiting a Surface of 38.5 mm²)

The filmed tablets are placed in an appropriate vibrator-distributorwhich orients and distributes the tablets singularly on suitably precisehousings with calibrated dimensions. A transport system allows thecarrying of the single tablets positioned on the maximal stabilitysurface under the ablation system constituted of a CO₂ laser beam sourcewith a power rating of 20 W which carries out the removal of a portionof the film. In particular, on the upper face of the filmed tablet isperformed a circular incision of 7.0 mm in diameter.

The incision is performed in a time of around 100 milliseconds, suchapplication necessary and sufficient to perforate the coating film of athickness of around 100 □m.

Operating as described above filmed tablets coated on every part of thesurface are obtained, with the exception of the cut surfaces asdescribed in FIG. 2. That means that all the coated surfaces of thetablets are impermeable to aqueous liquids with the exception of the cutsurfaces.

4.f—Dissolution Test;

To evaluate the release characteristics of the finished systems,described in 4.e (a circular incision of 7.0 mm in diameter) is used theapparatus 2, paddle (described in USP XXII) operating at 100 r.p.m. andusing 0.1 N hydrochloric acid at 37° C. as such dissolution fluid. Therelease of the active ingredient is followed by UV spectrophotometricdetermination at 236 nm using an automatic sampling and reading system(Spectracomp 602 from Advanced Products-Milan)

The results of the tests carried out are reported in Table IV TABLE IVTime (min) % release  15 21.4  30 48.3  60 51.1 120 51.8 180 52.0 21075.8 240 97.3 300 101.9

From the Table above, it is evident that a rapid release of the firstdose (50% of the total dose contained within the system) occurs in 15-30minutes, followed by an interval of around 2.5 hours during which nodrug is released and by the successive release of the second dose ofactive ingredient following approx. 4 from the start of the dissolutiontest. Such behaviour fully answers the objectives of the presentinvention.

EXAMPLE 5

The preparation of a series of 5000 three layered tablets as reported inFIG. 3, comprising such active ingredient in the first layer 50 mg ofhydrochlorothiazide, in the third layer 80 mg pf propanolol and abarrier layer.

5.a—Preparation of the Granulate Containing 50 mg of HydrochlorothiazideHydrochlorothiazide (Profarmaco -Milan)  50.0 mgHydroxypropylmethylcellulose (Methocel ® E  40.0 mg 15LV - Colorcon ®)Lactose (USP grade, C Erba, Milan, I)  40.0 mg Methylcellulose(Methocel ® A4 -  0.4 mg Colorcon ® - U.K) Magnesium stearate (C Erba,Milan, I)  1.0 mg Colloidal silica (Syloid ® 244, Grace GmbH, Worms, D 0.5 mg Total 131.9 mg

The envisaged amount of hydrochlorothiazide is mixed, in appropriatemixer, with hydroxypropylmethylcellulose and lactose; the homogeneousmixture obtained is humidified with an aqueous solution of 1.3%methylcellulose in water. The uniformly humidified mass is forcedthrough a 25 mesh grid (equal to 710 □m) obtaining a granulate which isdried in a hot air circulating oven until constant weight. The driedgranulate, re-calibrated through the same grid, is added to themagnesium stearate and the colloidal silica. The mass is mixed in a Vshaped mixer for 30 minutes.

The granulate thus obtained is used for the preparation of the firstlayer, as will be described in detail in the following point 1.c.

5.b—Preparation of a Granulate Containing 80 mg of PropanololPropranolol (Sigma -Milan)  80.0 mg Hydroxypropylmethylcellulose(Methocel ® E 50 LV -  50.0 mg Colorcon ®) Lactose (USP grade, C Erba,Milan, I)  50.0 mg Blue laquer (Colorcon ® - U.K)  1.0 mgMethylcellulose (Methocel ® A4- Colorcon ® - U.K)  0.4 mg Magnesiumstearate (C Erba, Milan, I)  1.0 mg Colloidal silica (Syloid ® 244,Grace GmbH, Worms, D  0.5 mg Total 182.9 mg

The envisaged amount of propanolol is mixed, in appropriate mixer, withhydroxypropylmethylcellulose and lactose and blue laquer; thehomogeneous mixture obtained, lightly green in colour, is humidifiedwith an aqueous solution of 1.3% methylcellulose in water. The uniformlyhumid mass is forced through a 25 mesh grid (equal to 710 □m) obtaininga granulate which is dried in a hot air circulating oven until constantweight. The dried granulate, re-calibrated through the same grille, isadded to the magnesium stearate and the colloidal silica. The mass ismixed in a V shaped mixture for 30 minutes.

The granulate thus obtained is used for the preparation of the thirdlayer, as will be described in detail in the following example 5.d.

5.c—Preparation of the Granulate for the Production of the Second Layer(Barrier Layer)

The granulate has the following percentage composition:Hydroxypropylmethylcellulose (Methocel ® E 50  76.5% LV - Colorcon ®-U.K.) Hydrogenated castor oil (Cutina ® HR -  19.0% Henkel -D)Polyvinylpyrrolidone (Povidone ISP-Wayne, NY,  2.9% USA) Orange laquer(Colorcon ® - U.K)  0.1% Stearic acid (C Erba, Milan, I)  1.5% Total100.0%

The envisaged amount of hydroxypropylmethylcellulose and hydrogenatedcastor oil are mixed, in an appropriate mixer, with the orange colouredlaquer; the homogeneous mixture obtained, lightly coloured, ishumidified with a hydroalcoholic solution of 10% polyvinylpyrrolidone.The uniformly humidified mass is forced through a 25 mesh grid (equal to710 □m) obtaining a granulate which is dried in a hot air circulatingoven to constant weight. The dried granulate, re-calibrated through thesame grille, is added to the stearic acid. The mass is mixed in a Vshaped mixer for 30 minutes.

The granulate thus obtained is used for the preparation of the secondlayer, as will be described in detail in the following point 5.d.

5.d—Preparation of the Three Layered Systems (by Compression).

The granulates obtained according to the above described procedures wellknown to any person skilled in the art, are loaded into three loadinghoppers of a rotary press suitable to produce three layered tablets(e.g. Manesty Layer-Press, Liverpool, UK). In particular in the firstand third hopper is loaded the granulate containing thehydrochlorothiazide, described in point 5.a; whilst in the second hopperis loaded the granulate constituting the intermediate barrier, describedin the preceding example 5.c and in the third hopper is loaded thegranulate containing the propanolol, described in example 5.b.

The machine press is fitted with rounded circular dies of 10.0 mm indiameter and radius of curvature=12 mm, allowing thus to obtain roundedcircular tablets.

The machine is set up so as to produce three layered systems constitutedrespectively of 131.9 mg of granulate containing 50 mg ofhydrochlorothiazide, 150.0 mg of the granulate prepared in the example5.c (such quantity being necessary to obtain a thickness of 1.5 mmapprox.) and 182.9 mg of the granulate containing 80 mg of propanolol.

Operating as described above, three layered tablets of mean weight of464.8 mg containing 50 mg of hydrochlorothiazide and 80 mg ofpropanolol, are obtained.

5.e—Coating for Filming.

The tablets thus obtained are subjected to film coating in a basin usingan ethanolic solution of ethylcellulose using diethylphthalate asplasticizer.

The filming operation is carried out in a traditional stainless steelbasin of 30 cm in diameter; the solution of polymeric coating materialis sprayed with a traditional air jet system (Asturo Mec type with anozzle of 1.0 mm). The filming operation is carried out until theapplication of a continuous, homogeneous and regular coating film isobtained for each tablet.

Operating in the described manner, completely coated three layeredtablets are obtained, as highlighted in FIG. 1.

5.f—Incision of the Film Coat (With Circular Incisions of 5.0 mm inDiameter Equal to 19.6 .mm²) on both Faces of the Tablet.

The filmed tablets are placed in an appropriate vibrator-distributorwhich orients and distributes the tablets singularly on suitably precisehousings with calibrated dimensions. A transport system allows thecarrying of the single tablets positioned on the maximal stabilitysurface under the ablation system constituted of a CO₂ laser beam sourcewith a power rating of 20 W which carries out the removal of a portionof the film. In particular on both faces of the filmed tablet areperformed circular incisions of 5.0 mm in diameter equal to 19.6 mm².

The incisions are carried out in a time of approx. 100 milliseconds, theapplication necessary and sufficient to perforate the coating film witha thickness of approx. 100 □m.

Operating as reported above, filmed tablets coated on every part of thesurface are obtained, with the exception of the cut surfaces asdescribed in FIG. 3. That means that all the coated surfaces of thetablet are impermeable to aqueous liquids with the exception of thesurfaces on which the film has been removed.

5.g.—Dissolution Test. (On Filmed Tablets a Circular Incision of 5.0 mmin Diameter)

To evaluate the release characteristics of the finished systems,outlined in 5.f is used the apparatus 2, paddle (described in USP XXII)operating at 100 r.p.m. and using distilled water at 37° C. as suchdissolution fluid. The release of the active ingredient is followed byspectrophotometric determination at 270 nm for the hydrochlorothiazideand at 290 nm for the propanolol, using an automatic sampling andreading system (Spectracomp 602 from Advanced Products-Milan)

The results of the tests performed are reported in the following TableV. TABLE V % release % release Time (min) hydrochlorothiazide propanolol  0 0 0  120 10.9 12.3  240 23.2 25.1  360 37.3 38.4  720 62.0 68.2  96072.4 82.5 1200 81.2 92.7 1440 88.8 96.9

From the Table above, a release of hydrochlorothiazide and of propanololin approx. 24 hours occurs, with a more or less linear kinetics for boththe active ingredients.

Such behaviour completely answers the objectives of the presentinvention.

EXAMPLE 6

Preparation of a series of 5000 filmed tablets, with three layers asdescribed in FIG. 3, comprising as the active ingredient in the firstlayer 50 mg of hydrochlorothiazide, in the third layer 80 mg ofpropanolol and an intermediate barrier layer.

The difference with respect to Example 5 consists in the greater surfaceof the film delimited by the incisions (38.5 mm² of surface).

The preparation of the filmed tablets is carried out exactly asdescribed in Examples 5.a to 5.e.

6-f Incision of the Film, Coating (With a Circular Incision of 7.0 mm inDiameter Equal to an area of 38.5 mm²) on Both Faces of the Tablet

The filmed tablets are placed in an appropriate vibrator-distributorwhich serves to orient and distribute the tablets singularly on suitablyprecise housings with calibrated dimensions. A transport system allowsthe carrying of the single tablets positioned on the maximal stabilitysurface under the ablation system constituted of a CO₂ laser beam sourcewith a power rating of 20 W which carries out the removal of a portionof the film. In particular on both faces of the filmed tablet areperformed a circular incision of 7.0 mm in diameter.

The incision is carried out in a time of approx. 100 milliseconds, theapplication necessary and sufficient to perforate the coating film witha thickness of approx. 100 □m.

Operating as described above, filmed tablets coated on every part of thesurface are obtained, with the exception of the surfaces cut asdescribed in FIG. 3. That means that all the coated surface of thetablet is impermeable to aqueous liquids with the exception of the cutsurfaces.

6.g—Dissolution Test. (On Filmed Tablets with Circular Incisions of 7.0mm in Diameter)

To evaluate the release characteristics of the finished systems,described in Example 6-f is used the apparatus 2, paddle (described inUSP XXII) operating at 100 r.p.m. and using distilled water at 37° C. assuch dissolution fluid. The release of the active ingredient is followedby UV spectrophotometric determination at 270 nm for thehydrochlorothiazide and at 290 nm for the propanolol, using an automaticsampling and reading system (Spectracomp 602 from AdvancedProducts-Milan).

The results of the tests carried out are reported in the following TableVI. TABLE VI % release % release Time (min) Hydrochlorothiazidepropanolol   0 0 0  120 15.3 21.6  240 35.8 36.9  360 56.4 54.3  72077.0 86.3  960 85.3 96.2 1200 92.8 98.8 1440 99.8 99.8

From the Table above, it comes out that a release of hydrochlorothiazideand propanolol occurs with a more or less linear kinetics for both theactive ingredients. In addition the release of the active ingredients isnotably faster with respect to tablets which have free circular surfacesof 5.0 mm in diameter equal to 19.6 mm² of free surface on each face ofthe tablet.

Such behaviour completely answers the objectives of the presentinvention.

1. Therapeutic system for the controlled release of one or more activeingredients, with previously programmed passage, characterised by thefact that it comprises a nucleus constituted of a three layered tabletof which the two external layers vehicularise the active ingredient(s)whilst the internal layer is constituted of a polymeric barrier erodibleor gelable in aqueous means, said tablet being completely coated by afilm of polymeric material insoluble in aqueous fluids, on which havebeen carried out by laser one or more incisions delimiting an area ofgeometric shape and predetermined dimensions as a function of therelease times which it is desired to obtain, said release taking placefrom the area of the nucleus underlying the surfaces of the film coatingdelimited by the incisions, which are detached when the therapeuticsystem comes into contact with aqueous fluids.
 2. Therapeutic systemaccording to claim 1, in which the coating film is incised only incorrespondence with the first layer of the tablet (nucleus). 3.Therapeutic system according to claim 1, in which the film coating isincised in correspondence both with the first and the third layer. 4.Therapeutic system according to claim 2, in which both the first and thethird layer comprise the same active ingredient.
 5. Therapeutic systemaccording to claim 2, in which the first and the third layer comprisedifferent active ingredients.
 6. Therapeutic system according to claim3, in which the first and the third layer comprise different activeingredients.
 7. Therapeutic system according to claim 1, in which thefirst and the third layer have an identical composition for thecontrolled release of the active ingredient.
 8. Therapeutic systemaccording to claim 1, in which the first and third layer have differentcompositions for the controlled release of the active ingredient. 9.Therapeutic system according to claim 1, in which the area delimited bythe incision(s) on the insoluble coating film has dimensions comprisedof between 2 and 50% of the total area of the coating.
 10. Therapeuticsystem according to claim 9, in which the area delimited by theincision(s) on the insoluble coating film is of dimensions comprised ofbetween 5 and 30% of the total area of the coating.
 11. Therapeuticsystem according to claim 1, in which the first layer comprises one ormore polymers able to modulate the release of the active ingredient. 12.Therapeutic system according to claim 11, in which said polymersconstitute between 1% and 90in weight of said layer.
 13. Therapeuticsystem according to claim 12, in which said polymers constitute between5% and 60% in weight of said layer.
 14. Therapeutic system according toclaim 1, in which the first layer comprises excipients capable ofaccelerating the release of the active ingredient(s).
 15. Therapeuticsystem according to claim 14, in which said excipients are disintegrantsor effervescent mixtures.
 16. Therapeutic system according to claim 1,in which the third layer comprises one or more polymers capable ofmodulating the release of the active ingredient(s).
 17. Therapeuticsystem according to claim 16, in which said polymers constitute between1% and 90% in weight of said layer.
 18. Therapeutic system according toclaim 17, in which said polymers constitute between 5% and 60% in weightof said layer.
 19. Therapeutic system according to claim 1, in which thethird layer comprises excipients able to accelerate the release of theactive ingredient.
 20. Therapeutic system according to claim 19, inwhich said excipients are disaggregants or effervescent mixtures. 21.Therapeutic system according to claim 1, in which the second layercomprises one or more polymers selected from predominantly erodiblepolymers and predominantly gelifyable polymers.
 22. Therapeutic systemaccording to claim 21, in which said polymers constitute between 5 and90% in weight of said layer.
 23. Therapeutic system according to claim22, in which said polymers constitute from 30 to 90% in weight of saidlayer.
 24. Therapeutic system according to claim 1, in which said threelayers each have a thickness comprised of between 0.5 and 5 mm. 25.Therapeutic system according to claim 1, in which on the insolublepolymeric coating film a second gastroresistant and enterosolublepolymeric coating film is applied.
 26. Process for the preparation ofthe therapeutic system according to claim 1, characterised by the factthat the incision(s) on the coating film are performed by the use of alaser beam.
 27. Process according to claim 26, in which the incision(s)on the coating film are performed with a CO₂ source laser device havingan output of 20 W.